Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

Figures & data

Table 1 Pharmacological mechanisms and clinical symptoms of opioid-induced bowel dysfunction

Pharmacological mechanisms	Clinical symptoms
Decreased saliva production	Xerostomia
Dysmotility of the lower esophageal sphincter	Gastro-esophageal reflux (or, rarely, dysphagia)
Decreased gastric secretion, emptying and motility	Delayed absorption of medication, upper abdominal discomfort
Disturbed fluid secretion and absorption	Constipation
Abnormal bowel motility, increased resting contractile tone in the	Straining, incomplete bowel evacuation, bloating, abdominal
small and large intestinal circular muscles, and sphincter dysfunction	distension, constipation
Increased amplitudes of non-propulsive segmental bowel contractions	Spasm, abdominal cramps and pain, stasis of luminal contents, and hard dry stool
Constriction of sphincter of Oddi	Biliary colic, epigastric discomfort, and pain
Increased anal sphincter tone and impaired reflex relaxation during rectal distension	Evacuation disorders
Diminished intestinal, pancreatic, and biliary secretion	Hard, dry stools
Abnormal bowel motility, increased fermentation and meteorism, opioid-induced hyperalgesia	Chronic visceral pain
Central effects of opioids	Nausea and vomiting, anorexia

Notes: Adapted from: Springer International Publishing AG; Drugs; Opioid-induced bowel dysfunction: pathophysiology and management; 72(14); 2012; 1847–1865; Brock C, Olesen SS, Olesen AE, Frøkjaer JB, Andresen T, Drewes AM; Copyright © Springer International Publishing AG 2012; with kind permission of Springer Science+Business Media.¹²

Table 2 The Bowel Function Index (BFI)

Item	Intensity
Ease of defecation during the last 7 days according to patient assessment
Feeling of incomplete bowel evacuation during the last 7 days according to patient assessment
Personal judgment of patient regarding constipation during the last 7 days

Note: Adapted from: Validation of the Bowel Function Index to detect clinically meaningful changes in opioid-induced constipation; Rentz AM, Yu R, Müller-Lissner S, Leyendecker P; Journal of Medical Economics; 2009; Copyright © 2009 Informa Healthcare; adapted by permission of the publisher Informa Healthcare.³⁶

Table 3 Patient assessment of constipation symptom questionnaire (PAC-SYM)

Domain	Item
Abdominal	• Discomfort in your stomach
	• Pain in your stomach
	• Bloating in your stomach
	• Stomach cramps
Rectal	• Painful bowel movements
	• Rectal burning during or after bowel movement
	• Rectal bleeding or tearing during or after bowel movement
Stool	• Incomplete bowel movements, like you did not “finish”
	• Bowel movements that were too hard
	• Bowel movements that were too small
	• Straining or squeezing to try to pass a bowel movement
	• Feeling like you had to pass a bowel movement but could not (“false alarm”)

Notes: PAC-SYM comprises three domains: abdominal, rectal, and stool symptom mechanisms. Responses are scored as 0, absence of symptoms; 1, mild symptoms; 2, moderate symptoms; 3, severe symptoms; and 4, very severe symptoms. Adapted with permission from: Slappendel R, Simpson K, Dubois D, Keininger DL; European Journal of Pain; John Wiley and Sons; Validation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back pain; 2006;10(3):209–217; Copyright © 1999–2015 John Wiley & Sons, Inc. All Rights Reserved.⁴⁰

Table 4 Patient assessment of constipation quality of life questionnaire (PAC-QOL)

Domain	Item
Worries and concerns	• Been increasingly bothered by not being able to have a bowel movement
	• Felt stressed by your condition
	• Been worried about not being able to have a bowel movement
	• Been worried about not knowing when you are going to be able to have a bowel movement
	• Been upset by your condition
	• Been worried that your condition will get worse
	• Felt less self-confident because of your condition
	• Felt that your body was not working properly
	• Felt irritable because of your condition
	• Felt in control of your situation
	• Felt obsessed by your condition
	• Had fewer bowel movements than you would like
Physical discomfort	• Felt bloated to the point of bursting
	• Felt heavy because of your constipation
	• Felt any physical discomfort
	• Felt the need to have bowel movement but not been able to
Psychological discomfort	• Been embarrassed to be with other people
	• Been embarrassed about staying in bathroom for so long when you were away from home
	• Been embarrassed about staying in bathroom so often when you were away from home
	• Been eating less and less because of not being able to have bowel movements
	• Been worried about not being able to choose what you eat
	• Had to be careful what you eat
	• Been worried about having to change your daily routine
	• Had a decreased appetite
Satisfaction	• Satisfied with how often you have a bowel movement
	• Satisfied with the regularity of your bowel movements
	• Satisfied with the time it takes for food to pass through the intestines
	• Satisfied with your treatment

Notes: PAC-QOL comprises four domains and 28 items, all evaluated by the patient on a 5-point (0 to 4) Likert scale ranging from 0, not at all or none of the time to 4, extremely or all of the time. Adapted with permission from: Development and validation of the Patient Assessment of Constipa tion Quality of Life questionnaire; Marquis P, De La Loge C, Dubois D, McDermott A, Chassany O; Scandinavian Journal of Gastroenterology. 2005; Copyright © 2005 Informa Healthcare; 40(5):540–551; reprinted by permission of the publisher Informa Healthcare.⁴¹

Table 5 Pharmacological management of opioid-induced bowel dysfunction

Treatment	Pharmacological mechanisms	Drugs
Prokinetics, D2 receptor antagonists	Improve motility of the upper GI tract, increase lower esophageal sphincter tone	Metoclopramide, domperidone
	Improve motility of the whole GI tract due to inhibition of acetylcholinesterase	Itopride
Prokinetics, 5-HT4 receptor agonist	Improve GI motility	Tegaserod, cisapride – both drugs withdrawn due to cardiotoxicity Prucalopride
Prokinetics, chloride channels agonists	Stimulation of intestinal fluid secretion inducing softer stools, increased colonic transit and stool frequency	Lubiprostone
Prokinetics activating guanylate cyclase C	Stimulation of GI secretion and transit – increase stool frequency, stool weight, and ease stool passage	Linaclotide
Laxatives, stimulants	Activation of myenteric plexus in the colon – promotion of propulsive motility	Sennosides, bisacodyl
Laxatives – osmotic agents: saccharines (sugar alcohols)	Metabolism to short-chain fatty acids by gut bacteria	Lactulose, sorbitol
Laxatives – osmotic agents: macrogol	Decrease GI transit time	Polyethylene glycol 3350
Laxatives – osmotic agents: magnesium and sodium salts	Secretion of fluid into intestinal lumen	Magnesium hydroxide, sodium biphosphate
Laxatives – detergents	Increase GI secretion and decrease surface tension	Docusate
Opioid receptor agonists + opioid receptor antagonists	Targeting peripheral µ-opioid receptors, without affecting analgesia due to naloxone inactivation in the liver	Combined prolonged-release oxycodone/prolonged-release naloxone tablets
Purely peripheral acting µ-opioid receptor antagonists	Targeting of peripheral of µ-opioid receptor, without affecting analgesia due its inability to cross the blood–brain barrier	Methylnaltrexone, naloxegol Alvimopan – approved in the US only to accelerate the time to upper and lower GI recovery after partial large or small bowel resection surgery with primary anastomosis

Notes: Adapted from Rauck RL. Treatment of opioid-induced constipation: focus on the peripheral μ-opioid receptor antagonist methylnaltrexone. Drugs. 2013; 73(12):1297–1306.⁴⁴

Abbreviation: GI, gastrointestinal.

Figure 1 Chemical structures of oxycodone and naloxone.

Figure 2 Mechanisms of action of opioid agonist/antagonist combinations to counteract opioid-induced bowel dysfunction development.

Abbreviation: CNS, central nervous system.

Table 6 Mechanisms of action of purely peripherally acting µ-opioid receptor antagonists (PAMORA)

Place of action	Opioid agonists’ effects	Opioid antagonists’ effects
Central nervous system	Analgesia	No effect on analgesia
	Nausea
	Vomiting
	Sedation
	Decreased sensation of dyspnea
Blood–brain barrier
Enteric nervous system	Decreased gastric secretion, emptying and motility	PAMORA eg, methylnaltrexone, naloxegol
	Inhibition of propulsive intestinal contractions	Inhibition of opioid-induced gastrointestinal adverse effects
	Diminished intestinal, pancreatic and biliary secretion
	Increased absorption of fluids and electrolytes
	Increased anal sphincter tone
	Constipation

Notes: Adapted from Springer International Publishing AG; Journal of Gastroenterology; Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives; 49(1); 2014; 24–45; Sobczak M, Salaga M, Storr MA, Fichna J. Copyright © The Authors 2013; with kind permission of Springer Science+Business Media.¹⁰⁴

Figure 3 Chemical structures of naloxone, methylnaltrexone, alvimopan, and naloxegol.

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RentzAMYuRMüller-LissnerSLeyendeckerPValidation of the Bowel Function Index to detect clinically meaningful changes in opioid-induced constipationJ Med Econ200912437138319912069

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SlappendelRSimpsonKDuboisDKeiningerDLValidation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back painEur J Pain200610320921715914049

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MarquisPDe La LogeCDuboisDMcDermottAChassanyODevelopment and validation of the Patient Assessment of Constipation Quality of Life questionnaireScand J Gastroenterol200540554055116036506

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RauckRLTreatment of opioid-induced constipation: focus on the peripheral µ-opioid receptor antagonist methylnaltrexoneDrugs201373121297130623881667

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SobczakMSalagaMStorrMAFichnaJPhysiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectivesJ Gastroenterol2014491244523397116

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